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Abstract:

Optionally substituted (1- or 3-oxy)-4,5,7,8-tetrahydro-(optionally
4-oxo, 4-thioxo or 4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or
(1- or 3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or
4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine compounds, processes
for their production, their use as pharmaceuticals and pharmaceutical
compositions comprising the same.

Claims:

1. An optionally substituted (1- or 3-oxy)-4,5,7,8-tetrahydro-(optionally
4-oxo, 4-thioxo or 4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or
(1- or 3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or
4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, in free or salt
form.

3. The compound according to claim 1, wherein said compound is selected
from any one of the following: A) a Compound of Formula III-A or III-B:
##STR00028## wherein (i) Q is C(═O), C(═S), C(═N(R20))
or CH2; (ii) L is --O--; (iii) R1 is H or C1-6 alkyl
(e.g., methyl); (iv) R4 is H or C1-6 alkyl (e.g., methyl or
isopropyl) and R2 and R3 are, independently, H C1-6alkyl
(e.g., methyl, isopropyl) optionally substituted with halo or hydroxy
(e.g., R2 and R3 are both methyl, or R2 is H and R3
is methyl, ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl,
(optionally hetero)arylalkoxy, (optionally hetero)arylC1-6alkyl, or
R2 and R3 together form a 3-6-membered ring; or R2 is H
and R3 and R4 together form a di-, tri- or tetramethylene
bridge (pref. wherein the R3 and R4 together have the cis
configuration, e.g., where the carbons carrying R3 and R4 have
the R and S configurations, respectively); (v) R5 is a) -D-E-F,
wherein: D is C1-6alkylene (e.g., methylene, ethylene or
prop-2-yn-1-ylene); E is a single bond, C2-4alkynylene (e.g.,
--C≡C--), arylene (e.g., phenylene) or heteroarylene (e.g.,
pyridylene); F is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl,
diazolyl, triazolyl, for example, pyrid-2-yl, imidazol-1-yl,
1,2,4-triazol-1-yl), halo (e.g., F, Br, Cl), haloC1-6 alkyl (e.g.,
trifluoromethyl), C1-6alkoxy (e.g., methoxy), --C(O)--R15,
--N(R16)(R17), or C3-7cycloalkyl optionally containing at
least one atom selected from a group consisting of N or O (e.g.,
cyclopentyl, cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl),
tetrahydro-2H-pyran-4-yl, or morpholinyl); wherein D, E and F are
independently and optionally substituted with one or more halo (e.g., F,
Cl or Br), C1-6 alkyl (e.g., methyl), haloC1-6alkyl (e.g.,
trifluoromethyl), C1-6alkoxy (e.g., methoxy), hydroxy,
C1-6carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or
pyridylphenyl), for example, F is heteroaryl, e.g., pyridyl substituted
with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl,
6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,
4,6-dichloropyrid-2-yl), haloC1-6alkyl (e.g.,
5-trifluoromethylpyrid-2-yl) or C1-6alkyl (e.g.,
5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with one or
more halo (e.g., 4-fluorophenyl) or F is a C3-7heterocycloalkyl
(e.g., pyrrolidinyl) optionally substituted with a C1-6alkyl (e.g.,
1-methylpyrrolidin-3-yl or 1-methylpyrrolidin-2-yl); or b) a substituted
heteroarylalkyl, e.g., substituted with haloC1-6alkyl; c) attached
to the nitrogen on the pyrrolo portion of Formula III-A or III-B and is a
moiety of Formula A ##STR00029## wherein X, Y and Z are,
independently, N or C, and R8, R9, R11 and R12 are
independently H or halogen (e.g., Cl or F), and R10 is halogen,
C1-6alkyl, haloC1-6alkyl (e.g., trifluoromethyl)
C1-6alkoxy (e.g. methoxy), C3-7cycloalkyl,
heteroC3-7cycloalkyl (e.g., pyrrolidinyl or piperidinyl), hetero
C1-6haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
heteroaryl (e.g., pyridyl (for example pyrid-2-yl or pyrid-4-yl), or
thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,
imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,
arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl),
heteroarylcarbonyl, or alkoxycarbonyl; wherein the aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is independently, optionally substituted
with one or more C1-6alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC1-6alkyl (e.g., trifluoromethyl), hydroxy,
C1-6-carboxy, --SH or an additional aryl or heteroaryl (e.g.,
biphenyl or pyridylphenyl), provided that when X, Y, or Z is nitrogen,
R8, R9, or R10, respectively, is not present; (vi) R6
is C1-6alkyl (e.g., isopropyl), C3-7cycloalkyl (e.g.,
cyclopentyl or cyclohexyl), aryl (e.g., phenyl), heteroaryl (e.g.,
pyridyl, for example, pyrid-4-yl), or arylC1-6alkyl (e.g., benzyl),
wherein the aryl or heteroaryl is optionally substituted with one or more
group selected from halo (e.g., F, Cl), hydroxy, C1-6alkyl,
C1-6alkoxy and C3-8cycloalkyl, for example, R6 is
3-chlorophenyl or 4-fluorophenyl; (vii) R7 is H, C1-6alkyl
(e.g., methyl or ethyl), halogen (e.g., Cl), --N(R18)(R19),
hydroxy or C1-6alkoxy; (viii) n=0 or 1; (ix) when n=1, A is
--C(R13R14)--, wherein R13 and R14, are,
independently, H or C1-6alkyl, aryl, heteroaryl, (optionally
hetero)arylC1-6alkoxy, (optionally hetero)arylC1-6alkyl or
R14 can form a bridge with R2 or R4; (x) R15 is --OH
or --OC1-6alkyl (e.g., --OCH3); (xi) R16 and R17 are
independently H or C1-6alkyl; (xii) R18 and R19 are
independently H, C1-6alky (e.g., methyl, ethyl, n-propyl, isobutyl),
C3-8cycloalkyl (e.g., cyclohexyl or cyclopenyl),
heteroC3-8cycloalkyl (e.g., pyrrolidinyl, piperidinyl, morpholinyl),
aryl (e.g., phenyl) or heteroaryl, wherein said aryl and heteroaryl are
optionally substituted with one or more halo (e.g., fluorophenyl, e.g.,
4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or
2-hydroxyphenyl) C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g.,
trifluoromethyl), C1-6-carboxy, or an additional aryl, heteroaryl
(e.g., biphenyl or pyridylphenyl) or C3-8cycloalkyl; (xiii) R20
is H, C1-6alkyl or C3-7cycloalkyl; in free or salt form; B) a
Compound of Formula IV-A or IV-B: ##STR00030## wherein (i) Q is
C(═O), C(═S), C(═N(R20)) or CH2; (ii) L is --O--;
(iii) R1 is H or C1-6 alkyl (e.g., methyl); (iv) R4 is H
or C1-6 alkyl (e.g., methyl or isopropyl) and R2 and R3
are, independently, H C1-6alkyl (e.g., methyl, isopropyl) optionally
substituted with halo or hydroxy (e.g., R2 and R3 are both
methyl, or R2 is H and R3 is methyl, ethyl, isopropyl or
hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy,
(optionally hetero)arylC1-6alkyl, or R2 and R3 together
form a 3- to 6-membered ring; or R2 is H and R3 and R4
together form a di-, tri- or tetramethylene bridge (pref. wherein the
R3 and R4 together have the cis configuration, e.g., where the
carbons carrying R3 and R4 have the R and S configurations,
respectively); (v) R5 is attached to the nitrogen on the pyrrolo
portion of Formula IV-A or IV-B and is a moiety of Formula A
##STR00031## wherein X, Y and Z are, independently, N or C, and
R8, R9, R11 and R12 are independently H or halogen
(e.g., Cl or F), and R10 is halogen, C1-6alkyl, C1-6alkoxy
(e.g., methoxy), haloC1-6alkyl (e.g., trifluoromethyl)
C1-6alkoxy (e.g. methoxy), C3-7cycloalkyl,
heteroC3-7cycloalkyl (e.g., pyrrolidinyl or piperidinyl),
C1-6haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
heteroaryl (e.g., pyridyl (for example pyrid-2-yl or pyrid-4-yl), or
thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,
imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,
arylcarbonyl (e.g., benzoyl), C1-6alkylsulfonyl (e.g.,
methylsulfonyl), heteroarylcarbonyl, or C1-6alkoxycarbonyl; wherein
the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is independently,
optionally substituted with one or more C1-6alkyl (e.g., methyl),
halogen (e.g., chloro or fluoro), haloC1-6alkyl (e.g.,
trifluoromethyl), hydroxy, C1-6-carboxy, --SH or an additional aryl
or heteroaryl (e.g., biphenyl or pyridylphenyl), provided that when X, Y,
or Z is nitrogen, R8, R9, or R10, respectively, is not
present; (vi) R6 is C1-6 alkyl (e.g., isopropyl),
C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl (e.g.,
phenyl), heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or
arylC1-6alkyl (e.g., benzyl), wherein the aryl or heteroaryl is
optionally substituted with one or more group selected from halo (e.g.,
F, Cl), hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl,
for example, R6 is 3-chlorophenyl or 4-fluorophenyl; (vii) R7
is H; (viii) n=0 or 1; (ix) when n=1, A is --C(R13R14)--,
wherein R13 and R14, are, independently, H or C1-6alkyl,
aryl, heteroaryl, (optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; (x) R20 is H, C1-6alkyl or C3-7cycloalkyl; in
free or salt form; C) a Compound of Formula V-A or V-B: ##STR00032##
wherein (i) Q is C(═O); (ii) L is --O--; (iii) R1 is H or
C1-6 alkyl (e.g., methyl); (iv) R4 is H or C1-6 alkyl
(e.g., methyl or isopropyl) and R2 and R3 are, independently, H
C1-6alkyl (e.g., methyl, isopropyl) optionally substituted with halo
or hydroxy (e.g., R2 and R3 are both methyl, or R2 is H
and R3 is methyl, ethyl, isopropyl or hydroxyethyl), aryl,
heteroaryl, (optionally hetero)arylalkoxy, (optionally
hetero)arylC1-6alkyl, or R2 and R3 together form a 3- to
6-membered ring; or R2 is H and R3 and R4 together form a
di-, tri- or tetramethylene bridge (pref. wherein the R3 and R4
together have the cis configuration, e.g., where the carbons carrying
R3 and R4 have the R and S configurations, respectively); (v)
R5 is attached to the nitrogen on the pyrrolo portion of Formula V-A
or V-B and is a moiety of Formula A ##STR00033## wherein X, Y and Z
are, independently, N or C, and R8, R9, R11 and R12
are independently H or halogen (e.g., Cl or F), and R10 is
C1-6alkoxy (e.g., methoxy), C3-7cycloalkyl,
heteroC3-7cycloalkyl (e.g., pyrrolidinyl or piperidinyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl or
pyrid-4-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl
(e.g., imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,
wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is
independently, optionally substituted with one or more C1-6alkyl
(e.g., methyl), halogen (e.g., chloro or fluoro), haloC1-6alkyl
(e.g., trifluoromethyl), hydroxy, C1-6-carboxy, --SH or an
additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), provided
that when X, Y, or Z is nitrogen, R8, R9, or R10,
respectively, is not present; (vi) R6 is C1-6alkyl (e.g.,
isopropyl), C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or
arylC1-6alkyl (e.g., benzyl), wherein the aryl or heteroaryl is
optionally substituted with one or more group selected from halo (e.g.,
F, Cl), hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl,
for example, R6 is 3-chlorophenyl or 4-fluorophenyl; (vii) R7
is H; (viii) n=0 or 1; and (ix) when n=1, A is --C(R13R14)--,
wherein R13 and R14, are, independently, H or C1-6alkyl,
aryl, heteroaryl, (optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form; D) a Compound of Formula VI-A or VI-B
##STR00034## wherein (i) Q is C(═O); (ii) L is --O--; (iii) R1
is H or C1-6 alkyl (e.g., methyl); (iv) R4 is H or C1-6
alkyl (e.g., methyl or isopropyl) and R2 and R3 are,
independently, H C1-6alkyl (e.g., methyl, isopropyl) optionally
substituted with halo or hydroxy (e.g., R2 and R3 are both
methyl, or R2 is H and R3 is methyl, ethyl, isopropyl or
hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy,
(optionally hetero)arylC1-6alkyl, or R2 and R3 together
form a 3- to 6-membered ring; or R2 is H and R3 and R4
together form a di-, tri- or tetramethylene bridge (pref. wherein the
R3 and R4 together have the cis configuration, e.g., where the
carbons carrying R3 and R4 have the R and S configurations,
respectively); (v) R5 is attached to the nitrogen on the pyrrolo
portion of Formula IV-A or IV-B and is a moiety of Formula A
##STR00035## wherein X, Y and Z are, independently, N or C, and
R8, R9, R11 and R12 are independently H or halogen
(e.g., Cl or F), and R10 is C1-6alkoxy (e.g., methoxy),
C3-7cycloalkyl, heteroC3-7cycloalkyl (e.g., pyrrolidinyl or
piperidinyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example
pyrid-2-yl or pyrid-4-yl), or thiadiazolyl (e.g.,
1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl, wherein the aryl, heteroaryl, cycloalkyl
or heterocycloalkyl is independently, optionally substituted with one or
more C1-6alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),
haloC1-6alkyl (e.g., trifluoromethyl), hydroxy, C1-6-carboxy,
--SH or an additional aryl or heteroaryl (e.g., biphenyl or
pyridylphenyl), provided that when X, Y, or Z is nitrogen, R9,
R9, or R10, respectively, is not present; (vi) R6 is
C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl (e.g.,
phenyl), heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or wherein
the aryl or heteroaryl is optionally substituted with one or more group
selected from halo (e.g., F, Cl), hydroxy, C1-6alkyl,
C1-6alkoxy and C3-8cycloalkyl, for example, R6 is
3-chlorophenyl or 4-fluorophenyl; (vii) R7 is H; (viii) n=0 or 1;
and (ix) when n=1, A is --C(R13R14)--, wherein R13 and
R14, are, independently, H or C1-6alkyl, aryl, heteroaryl,
(optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form; E) a Compound of Formula VII-A or VII-B:
##STR00036## wherein (i) Q is C(═O); (ii) L is --O--; (iii) R1
is H or C1-6 alkyl (e.g., methyl); (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively); (v) R5 is attached to the nitrogen on the pyrrolo
portion of Formula VII-A or VII-B and is a moiety of Formula A
##STR00037## wherein X, Y and Z are, independently, N or C, and
R8, R9, R11 and R12 are independently H or halogen
(e.g., Cl or F), and R10 is C1-6alkoxy (e.g., methoxy),
C3-7cycloalkyl, heteroC3-7cycloalkyl (e.g., pyrrolidinyl or
piperidinyl),

aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl or
pyrid-4-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl
(e.g., imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,
wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is
independently, optionally substituted with one or more C1-6alkyl
(e.g., methyl), halogen (e.g., chloro or fluoro), haloC1-6alkyl
(e.g., trifluoromethyl), hydroxy, C1-6-carboxy, --SH or an
additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), provided
that when X, Y, or Z is nitrogen, R8, R9, or R10,
respectively, is not present; (vi) R6 is C1-6 alkyl (e.g.,
isopropyl), C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or
arylC1-6alkyl (e.g., benzyl), wherein the aryl or heteroaryl is
optionally substituted with one or more group selected from halo (e.g.,
F, Cl), hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl,
for example, R6 is 3-chlorophenyl or 4-fluorophenyl; (vii) R7
is H; (viii) n=0 or 1; and (ix) when n=1, A is --C(R13R14)--,
wherein R13 and R14, are, independently, H or C1-6alkyl,
aryl, heteroaryl, (optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form; F) a Compound of Formula VIII-A or VIII-B:
##STR00038## wherein (i) Q is C(═O); (ii) L is --O--; (iii) R1
is H or C1-6 alkyl (e.g., methyl); (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively); (v) R5 is attached to the nitrogen on the pyrrolo
portion of Formula VIII-A or VIII-B and is a moiety of Formula A
##STR00039## wherein X, Y and Z are, C; R8, R9, R11 and
R12 are H; and R10 is heteroC3-7cycloalkyl (e.g.,
pyrrolidinyl or piperidinyl), heteroaryl (e.g., pyridyl (for example
pyrid-2-yl or pyrid-4-yl), or thiadiazolyl (e.g.,
1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl, wherein the heteroaryl or
heterocycloalkyl is independently, optionally substituted with one or
more C1-6alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),
(vi) R6 is C1-6 alkyl (e.g., isopropyl), C3-7cycloalkyl
(e.g., cyclopentyl or cyclohexyl), aryl (e.g., phenyl), heteroaryl (e.g.,
pyridyl, for example, pyrid-4-yl), or arylC1-6alkyl (e.g., benzyl),
wherein the aryl or heteroaryl is optionally substituted with one or more
group selected from halo (e.g., F, Cl), hydroxy, C1-6alkyl,
C1-6alkoxy and C3-8cycloalkyl, for example, R6 is
3-chlorophenyl or 4-fluorophenyl; (vii) R7 is H; (viii) n=0 or 1;
and (ix) when n=1, A is --C(R13R14)--, wherein R13 and
R14, are, independently, H or C1-6alkyl, aryl, heteroaryl,
(optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form; G) a Compound of Formula IX-A or IX-B
##STR00040## wherein (i) Q is C(═O); (ii) L is --O--; (iii) R1
is H or C1-6 alkyl (e.g., methyl); (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively); (v) R5 is attached to the nitrogen on the pyrrolo
portion of Formula IX-A or IX-B and is a moiety of Formula A
##STR00041## wherein X, Y and Z are, C; R8, R9, R11 and
R12 are H; and R10 is selected from the following:
pyrrolidinyl, piperidinyl, pyridyl (for example pyrid-2-yl or
pyrid-4-yl), thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,
imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl, wherein
R10 is optionally substituted with one or more C1-6alkyl (e.g.,
methyl), halogen (e.g., chloro or fluoro), for example 6-fluoropyrid-2-yl
or 1-methylpyrrolidin-2-yl; (vi) R6 is C1-6alkyl (e.g.,
isopropyl), C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or
arylC1-6alkyl (e.g., benzyl), wherein the aryl or heteroaryl is
optionally substituted with one or more group selected from halo (e.g.,
F, Cl), hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl,
for example, R6 is 3-chlorophenyl or 4-fluorophenyl; (vii) R7
is H; (viii) n=0 or 1; and (ix) when n=1, A is --C(R13R14)--,
wherein R13 and R14, are, independently, H or C1-6alkyl,
aryl, heteroaryl, (optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form; H) a Compound of Formula X-A or X-B
##STR00042## wherein (i) Q is C(═O); (ii) L is --O--; (iii) R1
is H or C1-6 alkyl (e.g., methyl); (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively); (v) R5 is attached to the nitrogen on the pyrrolo
portion of Formula X-A or X-B and is a moiety of Formula A ##STR00043##
wherein X, Y and Z are, C; R8, R9, R11 and R12 are
H; and R10 is pyrid-2-yl, 1,2,4-triazolyl, 6-fluoropyrid-2-yl or
1-methylpyrrolidin-2-yl; (vi) R6 is C1-6 alkyl (e.g.,
isopropyl), C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or
arylC1-6alkyl (e.g., benzyl), wherein the aryl or heteroaryl is
optionally substituted with one or more group selected from halo (e.g.,
F, Cl), hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl,
for example, R6 is 3-chlorophenyl or 4-fluorophenyl; (vii) R7
is H; (viii) n=0 or 1; and (ix) when n=1, A is --C(R13R14)--,
wherein R13 and R14, are, independently, H or C1-6alkyl,
aryl, heteroaryl, (optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form; I) a Compound of Formula XI-A or XI-B
##STR00044## wherein (i) Q is C(═O); (ii) L is --O--; (iii) R1
is H or C1-6 alkyl (e.g., methyl); (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively); (v) R5 is attached to the nitrogen on the pyrrolo
portion of Formula XI-A or XI-B and is a moiety of Formula A
##STR00045## wherein X, Y and Z are, C; R8, R9, R11 and
R12 are H; and R10 C1-6alkoxy (e.g. methoxy); (vi) R6
is aryl (e.g., phenyl); (vii) R7 is H; (viii) n=0, in free or salt
form.

4. The compound according to claim 1, wherein said compound is:
##STR00046## in free or salt form.

5. A pharmaceutical composition comprising a compound according to claim
1, in free or pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier.

6. The pharmaceutical composition according to claim 5, wherein the salt
and the diluents or carrier are ophthalmically acceptable.

8. The method of claim 7, wherein the condition is Parkinson's disease.

9. The method of claim 7, wherein the condition is cognitive impairment.

10. The method of claim 7, wherein the condition is narcolepsy.

11. The method of claim 10 further comprising administering a compound or
compounds selected from central nervous system stimulants, modafinil,
antidepressants, and gamma hydroxybutyrate, to a patient in need thereof.

12. The method of claim 7, wherein said condition is female sexual
dysfunction.

13. The method of claim 12, further comprising administering a compound
selected from a group consisting of estradiol, estriol, estradiol esters,
progesterone and progestins to a patient in need thereof.

14. A method for the treatment of glaucoma or elevated intraocular
pressure comprising topical administration of a therapeutically effective
amount of a compound according to claim 1, in free or pharmaceutically
acceptable salt form, in an ophthalmically compatible carrier to the eye
of a patient in need thereof.

15. A method for the treatment of psychosis, schizophrenia,
schizoaffective disorder, schizophreniform disorder, psychotic disorder,
delusional disorder, and mania, such as in acute manic episodes and
bipolar disorder, comprising administering a therapeutically effective
amount of a compound according to claim 1, in free or pharmaceutically
acceptable salt form, to a patient in need thereof.

16. A method for the treatment of traumatic brain injury comprising
administering to a patient in need thereof, a compound according to claim
1, in free or pharmaceutically acceptable salt form.

17. A method for lengthening or enhancing growth of the eyelashes by
administering an effective amount of a prostaglandin analogue, e.g.,
bimatoprost, concomitantly, simultaneously or sequentially with an
effective amount of a compound according to claim 1, in free or salt
form.

18. (canceled)

19. (canceled)

20. (canceled)

Description:

[0001] This application claims priority from U.S. Provisional Application
No. 61/349,960, filed May 31, 2010, the contents of which are hereby
incorporated by reference in their entirety.

TECHNICAL FIELD

[0002] The present invention relates to optionally substituted (1- or
3-oxy)-4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or
4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or (1- or
3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or
4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, for example,
compounds of Formula II (Formula II-A and II-B) as described below,
processes for their production, their use as pharmaceuticals and
pharmaceutical compositions comprising them. Of particular interest are
novel compounds useful as inhibitors of phosphodiesterase 1 (PDE1), e.g.,
in the treatment of diseases involving disorders of the dopamine D1
receptor intracellular pathway, such as Parkinson's disease, depression,
narcolepsy, damage to cognitive function, e.g., in schizophrenia, or
disorders that may be ameliorated through enhanced progesterone-signaling
pathway, e.g., female sexual dysfunction as well as other disease or
conditions characterized by low levels of cAMP and/or cGMP in cells
expressing PDE1 and those characterized by reduced dopamine D1 receptor
signaling activities.

BACKGROUND OF THE INVENTION

[0003] Eleven families of phosphodiesterases (PDEs) have been identified
but only PDEs in Family I, the Ca2+-calmodulin-dependent
phosphodiesterases (CaM-PDEs), have been shown to mediate both the
calcium and cyclic nucleotide (e.g. cAMP and cGMP) signaling pathways.
The three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed
in central nervous system tissue. PDE1A is expressed throughout the brain
with higher levels of expression in the CA1 to CA3 layers of the
hippocampus and cerebellum and at a low level in the striatum. PDE1A is
also expressed in the lung and heart. PDE1B is predominately expressed in
the striatum, dentate gyms, olfactory tract and cerebellum, and its
expression correlates with brain regions having high levels of
dopaminergic innervation. Although PDE1B is primarily expressed in the
central nervous system, it may be detected in the heart. PDE1C is
primarily expressed in olfactory epithelium, cerebellar granule cells,
and striatum. PDE1C is also expressed in the heart and vascular smooth
muscle.

[0004] Cyclic nucleotide phosphodiesterases decrease intracellular cAMP
and cGMP signaling by hydrolyzing these cyclic nucleotides to their
respective inactive 5'-monophosphates (5'AMP and 5'GMP). CaM-PDEs play a
critical role in mediating signal transduction in brain cells,
particularly within an area of the brain known as the basal ganglia or
striatum. For example, NMDA-type glutamate receptor activation and/or
dopamine D2 receptor activation result in increased intracellular calcium
concentrations, leading to activation of effectors such as
calmodulin-dependent kinase II (CaMKII) and calcineurin and to activation
of CaM-PDEs, resulting in reduced cAMP and cGMP. Dopamine D1 receptor
activation, on the other hand, leads to activation of nucleotide
cyclases, resulting in increased cAMP and cGMP. These cyclic nucleotides
in turn activate protein kinase A (PKA; cAMP-dependent protein kinase)
and/or protein kinase G (PKG; cGMP-dependent protein kinase) that
phosphorylate downstream signal transduction pathway elements such as
DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP responsive
element binding protein (CREB). Phosphorylated DARPP-32 in turn inhibits
the activity of protein phosphates-1 (PP-1), thereby increasing the state
of phosphorylation of substrate proteins such as progesterone receptor
(PR), leading to induction of physiologic responses. Studies in rodents
have suggested that inducing cAMP and cGMP synthesis through activation
of dopamine D1 or progesterone receptor enhances progesterone signaling
associated with various physiological responses, including the lordosis
response associated with receptivity to mating in some rodents. See Mani,
et al., Science (2000) 287: 1053, the contents of which are incorporated
herein by reference.

[0014] C1-6alkyl (e.g., methyl, isopropyl) optionally substituted
with halo or hydroxy (e.g., R2 and R3 are both methyl, or
R2 is H and R3 is methyl, ethyl, isopropyl or hydroxyethyl),

[0015] aryl,

[0016] heteroaryl,

[0017] (optionally hetero)arylalkoxy,

[0018] (optionally hetero)arylC1-6alkyl; or

[0019] R2 and
R3 together form a 3- to 6-membered ring;

[0020] or

[0021] R2
is H and R3 and R4 together form a di-, tri- or tetramethylene
bridge (pref. wherein the R3 and R4 together have the cis
configuration, e.g., where the carbons carrying R3 and R4 have
the R and S configurations, respectively);

[0036] C3-7cycloalkyl optionally
containing at least one atom selected from a group consisting of N or O
(e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl or
pyrrolidin-2-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl);

[0038] for example, F is heteroaryl,
e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC1-6alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C1-6 alkyl
(e.g., 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with
one or more halo (e.g., 4-fluorophenyl) or F is a
C3-7heterocycloalkyl (e.g., pyrrolidinyl or piperidinyl) optionally
substituted with a C1-6alkyl (e.g., 1-methylpyrrolidin-3-yl or
1-methylpyrrolidin-2-yl); or

[0057] provided that when X, Y, or Z is nitrogen,
R8, R9, or R10, respectively, is not present;

[0058]
(vi) R6 is

[0059] C1-6alkyl (e.g., isopropyl),

[0060]
C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl),

[0061] aryl (e.g.,
phenyl),

[0062] heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or

[0063] arylC1-6alkyl (e.g., benzyl),

[0064] wherein the aryl or
heteroaryl is optionally substituted with one or more group selected from
halo (e.g., F, Cl), hydroxy, C1-6alkyl, C1-6alkoxy and
C3-8cycloalkyl, for example, R6 is 3-chlorophenyl or
4-fluorophenyl;

[0067] (ix) when n=1, A is
--C(R13R14)--, wherein R13 and R14, are,
independently, H or C1-6alkyl, aryl, heteroaryl, (optionally
hetero)arylC1-6alkoxy, (optionally hetero)arylC1-6alkyl or
R14 can form a bridge with R2 or R4;

[0091] 1.6 Formula II-A or II-B, or any of
1.1-1.5, wherein L is --O--;

[0092] 1.7 Formula II-A or II-B, or any of
1.1-1.6, wherein R1 is H or C1-6 alkyl (e.g., methyl);

[0093]
1.8 Formula 1.7, wherein R1 is H,

[0094] 1.9 Formula 1.7, wherein
R1 is C1-6 alkyl (e.g., methyl);

[0095] 1.10 Formula II-A or
II-B, or any of 1.1-1.9, wherein R4 is H or C1-6 alkyl (e.g.,
methyl, isopropyl) and R2 and R3 are, independently,

[0096] H
or C1-6alkyl optionally substituted with halo or hydroxy (e.g.,
R2 and R3 are both methyl, or R2 is H and R3 is
methyl, ethyl, isopropyl or hydroxyethyl),

[0097] aryl,

[0098]
heteroaryl,

[0099] (optionally hetero)arylalkoxy, or

[0100] (optionally
hetero)arylC1-6alkyl;

[0101] 1.11 Formula II-A or II-B, or any of
1.1-1.9, wherein R2 is H and R3 and R4 together form a
di-, tri- or tetramethylene bridge (pref. wherein the R3 and R4
together have the cis configuration, e.g., where the carbons carrying
R3 and R4 have the R and S configurations, respectively);

[0102] 1.12 Formula II-A or II-B or any of 1.1-1.11, wherein R5 is
-D-E-F;

[0130] 1.40 Any of
formulae 1.12-1.39, wherein D, E and F are independently and optionally
substituted with one or more halo (e.g., F, Cl or Br), C1-6alkyl
(e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), for example,
F is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC1-6alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C1-6alkyl
(e.g., 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with
one or more halo (e.g., 4-fluorophenyl), or F is a
C3-7heterocycloalkyl (e.g., pyrrolidinyl) optionally substituted
with a C1-6alkyl (e.g., 1-methylpyrrolidin-3-yl or
1-methylpyrrolidin-2-yl);

[0161] wherein
the aryl or heteroaryl is optionally substituted with one or more group
selected from halo (e.g., F, Cl), hydroxy, C1-6alkyl,
C1-6alkoxy and C3-8cycloalkyl, for example, R6 is
3-chlorophenyl or 4-fluorophenyl;

[0191] 1.81 any of the preceding formulae wherein R20 is H,
C1-6alkyl or C3-7cycloalkyl;

[0192] 1.82 any of the preceding
formulae wherein R20 is H,

[0193] 1.83 any of the preceding formulae
wherein the compound is:

[0193] ##STR00004##

[0194] 1.84 any of the preceding formulae wherein
the compounds inhibit phosphodiesterase-mediated (e.g., PDE1-mediated,
especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC50 of
less than 1 μM, preferably less than 750 nM, more preferably less than
500 nM, more preferably less than 50 nM in an immobilized-metal affinity
particle reagent PDE assay, for example, as described in Example 2, in
free or salt form.

[0195] In a further embodiment, the Compound of Formula II-A or II-B as
defined above is a Compound of Formula III-A or III-B, wherein:

[0201]
C1-6alkyl (e.g., methyl, isopropyl) optionally substituted with halo
or hydroxy (e.g., R2 and R3 are both methyl, or R2 is H
and R3 is methyl, ethyl, isopropyl or hydroxyethyl),

[0202] aryl,

[0203] heteroaryl,

[0204] (optionally hetero)arylalkoxy,

[0205]
(optionally hetero)arylC1-6alkyl, or

[0206] R2 and R3
together form a 3-6-membered ring;

[0207] or

[0208] R2 is H and
R3 and R4 together form a di-, tri- or tetramethylene bridge
(pref. wherein the R3 and R4 together have the cis
configuration, e.g., where the carbons carrying R3 and R4 have
the R and S configurations, respectively);

[0224] for example, F is heteroaryl, e.g., pyridyl
substituted with one or more halo (e.g., 6-fluoropyrid-2-yl,
5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,
4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC1-6alkyl (e.g.,
5-trifluoromethylpyrid-2-yl) or C1-6alkyl (e.g.,
5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with one or
more halo (e.g., 4-fluorophenyl) or F is a C3-7heterocycloalkyl
(e.g., pyrrolidinyl) optionally substituted with a C1-6alkyl (e.g.,
1-methylpyrrolidin-3-yl or 1-methylpyrrolidin-2-yl); or

[0249] wherein the aryl or heteroaryl is optionally substituted
with one or more group selected from halo (e.g., F, Cl), hydroxy,
C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl, for example,
R6 is 3-chlorophenyl or 4-fluorophenyl;

[0252] (ix) when n=1, A is --C(R13R14)--, wherein R13
and R14, are, independently, H or C1-6alkyl, aryl, heteroaryl,
(optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4;

[0263]
C1-6alkyl (e.g., methyl, isopropyl) optionally substituted with halo
or hydroxy (e.g., R2 and R3 are both methyl, or R2 is H
and R3 is methyl, ethyl, isopropyl or hydroxyethyl),

[0264] aryl,

[0265] heteroaryl,

[0266] (optionally hetero)arylalkoxy,

[0267]
(optionally hetero)arylC1-6alkyl, or

[0268] R2 and R3
together form a 3- to 6-membered ring;

[0269] or

[0270] R2 is H and
R3 and R4 together form a di-, tri- or tetramethylene bridge
(pref. wherein the R3 and R4 together have the cis
configuration, e.g., where the carbons carrying R3 and R4 have
the R and S configurations, respectively);

[0271] (v) R5 is
attached to the nitrogen on the pyrrolo portion of Formula IV-A or IV-B
and is a moiety of Formula A

[0271] ##STR00006##

[0272] wherein X, Y and Z are, independently, N
or C, and R8, R9, R11 and R12 are independently H or
halogen (e.g., Cl or F), and R10 is

[0287] wherein
the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is independently,
optionally substituted with one or more C1-6alkyl (e.g., methyl),
halogen (e.g., chloro or fluoro), haloC1-6alkyl (e.g.,
trifluoromethyl), hydroxy, C1-6-carboxy, --SH or an additional aryl
or heteroaryl (e.g., biphenyl or pyridylphenyl),

[0288] provided that
when X, Y, or Z is nitrogen, R8, R9, or R10, respectively,
is not present;

[0289] (vi) R6 is

[0290] C1-6alkyl (e.g.,
isopropyl),

[0291] C3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl),

[0292] aryl (e.g., phenyl),

[0293] heteroaryl (e.g., pyridyl, for
example, pyrid-4-yl), or

[0294] arylC1-6alkyl (e.g., benzyl),

[0295]
wherein the aryl or heteroaryl is optionally substituted with one or more
group selected from halo (e.g., F, Cl), hydroxy, C1-6alkyl,
C1-6alkoxy and C3-8cycloalkyl, for example, R6 is
3-chlorophenyl or 4-fluorophenyl;

[0296] (vii) R7 is H;

[0297]
(viii) n=0 or 1;

[0298] (ix) when n=1, A is --C(R13R14)--,
wherein R13 and R14, are, independently, H or C1-6alkyl,
aryl, heteroaryl, (optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4;

[0299] (x) R20 is H, C1-6alkyl or C3-7cycloalkyl;
in free or salt form.

[0300] In yet another embodiment, the Compound of Formula II-A or II-B as
defined above is a Compound of Formula V-A or V-B, wherein:

[0306] C1-6alkyl (e.g., methyl, isopropyl)
optionally substituted with halo or hydroxy (e.g., R2 and R3
are both methyl, or R2 is H and R3 is methyl, ethyl, isopropyl
or hydroxyethyl),

[0307] aryl,

[0308] heteroaryl,

[0309] (optionally
hetero)arylalkoxy,

[0310] (optionally hetero)arylC1-6alkyl, or

[0311] R2 and R3 together form a 3- to 6-membered ring;

[0312]
or

[0313] R2 is H and R3 and R4 together form a di-, tri-
or tetramethylene bridge (pref. wherein the R3 and R4 together
have the cis configuration, e.g., where the carbons carrying R3 and
R4 have the R and S configurations, respectively);

[0314] (v)
R5 is attached to the nitrogen on the pyrrolo portion of Formula V-A
or V-B and is a moiety of Formula A

[0320] wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is
independently, optionally substituted with one or more C1-6alkyl
(e.g., methyl), halogen (e.g., chloro or fluoro), haloC1-6alkyl
(e.g., trifluoromethyl), hydroxy, C1-6-carboxy, --SH or an
additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl),

[0321]
provided that when X, Y, or Z is nitrogen, R8, R9, or R10,
respectively, is not present;

[0322] (vi) R6 is

[0323]
C1-6alkyl (e.g., isopropyl),

[0324] C3-7cycloalkyl (e.g.,
cyclopentyl or cyclohexyl),

[0325] aryl (e.g., phenyl),

[0326] heteroaryl
(e.g., pyridyl, for example, pyrid-4-yl), or

[0327] arylC1-6alkyl
(e.g., benzyl),

[0328] wherein the aryl or heteroaryl is optionally
substituted with one or more group selected from halo (e.g., F, Cl),
hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl, for
example, R6 is 3-chlorophenyl or 4-fluorophenyl;

[0329] (vii)
R7 is H;

[0330] (viii) n=0 or 1; and

[0331] (ix) when n=1, A is
--C(R13R14)--, wherein R13 and R14, are,
independently, H or C1-6alkyl, aryl, heteroaryl, (optionally
hetero)arylC1-6alkoxy, (optionally hetero)arylC1-6alkyl or
R14 can form a bridge with R2 or R4; in free or salt form.

[0332] In yet another embodiment, the Compound of Formula II-A or II-B as
defined above is a Compound of Formula VI-A or VI-B, wherein:

[0338] C1-6alkyl (e.g., methyl, isopropyl)
optionally substituted with halo or hydroxy (e.g., R2 and R3
are both methyl, or R2 is H and R3 is methyl, ethyl, isopropyl
or hydroxyethyl),

[0339] aryl,

[0340] heteroaryl,

[0341] (optionally
hetero)arylalkoxy,

[0342] (optionally hetero)arylC1-6alkyl, or

[0343] R2 and R3 together form a 3- to 6-membered ring;

[0344]
or

[0345] R2 is H and R3 and R4 together form a di-, tri-
or tetramethylene bridge (pref. wherein the R3 and R4 together
have the cis configuration, e.g., where the carbons carrying R3 and
R4 have the R and S configurations, respectively);

[0346] (v)
R5 is attached to the nitrogen on the pyrrolo portion of Formula
IV-A or IV-B and is a moiety of Formula A

[0354] wherein the aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is independently, optionally substituted
with one or more C1-6alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC1-6alkyl (e.g., trifluoromethyl), hydroxy,
C1-6-carboxy, --SH or an additional aryl or heteroaryl (e.g.,
biphenyl or pyridylphenyl),

[0355] provided that when X, Y, or Z is
nitrogen, R8, R9, or R10, respectively, is not present;

[0356] (vi) R6 is

[0357] C3-7cycloalkyl (e.g., cyclopentyl or
cyclohexyl),

[0358] aryl (e.g., phenyl),

[0359] heteroaryl (e.g.,
pyridyl, for example, pyrid-4-yl), or

[0360] wherein the aryl or
heteroaryl is optionally substituted with one or more group selected from
halo (e.g., F, CO, hydroxy, C1-6alkyl, C1-6alkoxy and
C3-8cycloalkyl, for example, R6 is 3-chlorophenyl or
4-fluorophenyl;

[0361] (vii) R7 is H;

[0362] (viii) n=0 or 1; and

[0363] (ix) when n=1, A is --C(R13R14)--, wherein R13 and
R14, are, independently, H or C1-6alkyl, aryl, heteroaryl,
(optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form.

[0364] In yet another embodiment, the Compound of Formula II-A or II-B as
defined above is a Compound of Formula VII-A or VII-B, wherein:

[0365]
(i) Q is C(═O);

[0366] (ii) L is --O--;

[0367] (iii) R1 is H or
C1-6 alkyl (e.g., methyl);

[0368] (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively);

[0369] (v) R5 is attached to the nitrogen on the
pyrrolo portion of Formula VII-A or VII-B and is a moiety of Formula A

[0369] ##STR00009##

[0370] wherein X, Y and Z are, independently, N
or C, and R8, R9, R11 and R12 are independently H or
halogen (e.g., Cl or F), and R10 is

[0376]
wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is
independently, optionally substituted with one or more C1-6alkyl
(e.g., methyl), halogen (e.g., chloro or fluoro), haloC1-6alkyl
(e.g., trifluoromethyl), hydroxy, C1-6-carboxy, --SH or an
additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl),

[0377]
provided that when X, Y, or Z is nitrogen, R8, R9, or R10,
respectively, is not present;

[0378] (vi) R6 is

[0379]
C1-6alkyl (e.g., isopropyl),

[0380] C3-7cycloalkyl (e.g.,
cyclopentyl or cyclohexyl),

[0381] aryl (e.g., phenyl),

[0382] heteroaryl
(e.g., pyridyl, for example, pyrid-4-yl), or

[0383] arylC1-6alkyl
(e.g., benzyl),

[0384] wherein the aryl or heteroaryl is optionally
substituted with one or more group selected from halo (e.g., F, Cl),
hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl, for
example, R6 is 3-chlorophenyl or 4-fluorophenyl;

[0385] (vii)
R7 is H;

[0386] (viii) n=0 or 1; and

[0387] (ix) when n=1, A is
--C(R13R14)--, wherein R13 and R14, are,
independently, H or C1-6alkyl, aryl, heteroaryl, (optionally
hetero)arylC1-6alkoxy, (optionally hetero)arylC1-6alkyl or
R14 can form a bridge with R2 or R4; in free or salt form.

[0388] In yet another embodiment, the Compound of Formula II-A or II-B as
defined above is a Compound of Formula VIII-A or VIII-B, wherein:

[0389] (i) Q is C(═O);

[0390] (ii) L is --O--;

[0391] (iii) R1
is H or C1-6 alkyl (e.g., methyl);

[0392] (iv) R2 is H and
R3 and R4 together form a di-, tri- or tetramethylene bridge
(pref. wherein the R3 and R4 together have the cis
configuration, e.g., where the carbons carrying R3 and R4 have
the R and S configurations, respectively);

[0393] (v) R5 is attached
to the nitrogen on the pyrrolo portion of Formula VIII-A or VIII-B and is
a moiety of Formula A

[0397] wherein the heteroaryl or heterocycloalkyl is independently,
optionally substituted with one or more C1-6alkyl (e.g., methyl),
halogen (e.g., chloro or fluoro),

[0398] (vi) R6 is

[0399]
C1-6alkyl (e.g., isopropyl),

[0400] C3-7cycloalkyl (e.g.,
cyclopentyl or cyclohexyl),

[0401] aryl (e.g., phenyl),

[0402] heteroaryl
(e.g., pyridyl, for example, pyrid-4-yl), or

[0403] arylC1-6alkyl
(e.g., benzyl),

[0404] wherein the aryl or heteroaryl is optionally
substituted with one or more group selected from halo (e.g., F, CO,
hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl, for
example, R6 is 3-chlorophenyl or 4-fluorophenyl;

[0405] (vii)
R7 is H;

[0406] (viii) n=0 or 1; and

[0407] (ix) when n=1, A is
--C(R13R14)--, wherein R13 and R14, are,
independently, H or C1-6alkyl, aryl, heteroaryl, (optionally
hetero)arylC1-6alkoxy, (optionally hetero)arylC1-6alkyl or
R14 can form a bridge with R2 or R4; in free or salt form.

[0408] In yet another embodiment, the Compound of Formula II-A or II-B as
defined above is a Compound of Formula IX-A or IX-B, wherein:

[0409]
(i) Q is C(═O);

[0410] (ii) L is --O--;

[0411] (iii) R1 is H or
C1-6 alkyl (e.g., methyl);

[0412] (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively);

[0413] (v) R5 is attached to the nitrogen on the
pyrrolo portion of Formula IX-A or IX-B and is a moiety of Formula A

[0421] wherein the aryl or heteroaryl is optionally
substituted with one or more group selected from halo (e.g., F, Cl),
hydroxy, C1-6alkyl, C1-6alkoxy and C3-8cycloalkyl, for
example, R6 is 3-chlorophenyl or 4-fluorophenyl;

[0422] (vii)
R7 is H;

[0423] (viii) n=0 or 1; and

[0424] (ix) when n=1, A is
--C(R13R14)--, wherein R13 and R14, are,
independently, H or C1-6alkyl, aryl, heteroaryl, (optionally
hetero)arylC1-6alkoxy, (optionally hetero)arylC1-6alkyl or
R14 can form a bridge with R2 or R4; in free or salt form.

[0425] In yet another embodiment, the Compound of Formula II-A or II-B as
defined above is a Compound of Formula X-A or X-B, wherein:

[0426] (i)
Q is C(═O);

[0427] (ii) L is --O--;

[0428] (iii) R1 is H or
C1-6 alkyl (e.g., methyl);

[0429] (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively);

[0430] (v) R5 is attached to the nitrogen on the
pyrrolo portion of Formula X-A or X-B and is a moiety of Formula A

[0438] wherein the aryl or
heteroaryl is optionally substituted with one or more group selected from
halo (e.g., F, CO, hydroxy, C1-6alkyl, C1-6alkoxy and
C3-8cycloalkyl, for example, R6 is 3-chlorophenyl or
4-fluorophenyl;

[0439] (vii) R7 is H;

[0440] (viii) n=0 or 1; and

[0441] (ix) when n=1, A is --C(R13R14)--, wherein R13 and
R14, are, independently, H or C1-6alkyl, aryl, heteroaryl,
(optionally hetero)arylC1-6alkoxy, (optionally
hetero)arylC1-6alkyl or R14 can form a bridge with R2 or
R4; in free or salt form.

[0442] In still another embodiment, the Compound of Formula II-A or II-B
as defined above is a Compound of Formula XI-A or XI-B, wherein:

[0443]
(i) Q is C(═O);

[0444] (ii) L is --O--;

[0445] (iii) R1 is H or
C1-6 alkyl (e.g., methyl);

[0446] (iv) R2 is H and R3 and
R4 together form a di-, tri- or tetramethylene bridge (pref. wherein
the R3 and R4 together have the cis configuration, e.g., where
the carbons carrying R3 and R4 have the R and S configurations,
respectively);

[0447] (v) R5 is attached to the nitrogen on the
pyrrolo portion of Formula XI-A or XI-B and is a moiety of Formula A

[0452] In still another embodiment, the compound of the invention, e.g.,
any of the compounds hereinbefore described is preferably a Compound of
Formula II-A, III-A, IV-A, V-A, VI-A, VII-A, VIII-A, IX-A, X-A or XI-A.

[0453] If not otherwise specified or clear from context, the following
terms herein have the following meanings:

[0454] (a) "Alkyl" as used
herein is a saturated or unsaturated hydrocarbon moiety, preferably
saturated, preferably having one to six carbon atoms, which may be linear
or branched, and may be optionally mono-, di- or tri-substituted, e.g.,
with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.

[0455] (b)
"Cycloalkyl" as used herein is a saturated or unsaturated nonaromatic
hydrocarbon moiety, preferably saturated, preferably comprising three to
nine carbon atoms, at least some of which form a nonaromatic mono- or
bicyclic, or bridged cyclic structure, and which may be optionally
substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or
carboxy. Wherein the cycloalkyl optionally contains one or more atoms
selected from N and O and/or S, said cycloalkyl may also be a
heterocycloalkyl.

[0456] (c) "Heterocycloalkyl" is, unless otherwise
indicated, saturated or unsaturated nonaromatic hydrocarbon moiety,
preferably saturated, preferably comprising three to nine carbon atoms,
at least some of which form a nonaromatic mono- or bicyclic, or bridged
cyclic structure, wherein at least one carbon atom is replaced with N, O
or S, which heterocycloalkyl may be optionally substituted, e.g., with
halogen (e.g., chloro or fluoro), hydroxy, or carboxy.

[0458] (e) "Heteroaryl" as used herein is an aromatic
moiety wherein one or more of the atoms making up the aromatic ring is
sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl,
which may be optionally substituted, e.g., with alkyl, halogen,
haloalkyl, hydroxy or carboxy.

[0459] (f) For ease of reference, the
atoms on the pyrazolo-pyrimidine core of the Compounds of the Invention
are numbered in accordance with the numbering depicted in Formula I,
unless otherwise noted.

[0460] (g) Wherein E is phenylene, the numbering
is as follows:

[0460] ##STR00014##

[0461] (h) It is intended that wherein the
substituents end in "ene", for example, alkylene, phenylene or
arylalkylene, said substituents are intended to bridge or be connected to
two other substituents. Therefore, methylene is intended to be
--CH2-- and phenylene intended to be --C6H4-- and
arylalkylene is intended to be --C6H4--CH2-- or
--CH2--C6H4--.

[0462] (i) The Compounds of the Invention
are intended to be numbered as follows:

##STR00015##

[0463] The term "substituted," as used herein, means that any one or more
hydrogens on the designated atom is replaced with a selection from the
indicated group, provided that the designated atom's normal valency is
not exceeded, and that the substitution results in a stable compound.
Similarly, the substituents defined for the Compounds of the Invention
are intended to result in stable compounds.

[0464] Compounds of the Invention, e.g., substituted
4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or
4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, e.g.,
Compounds of Formula II-A or II-B or any of formulae III-A or III-B
through XI-A or XI-B, or 1.1-1.84 may exist in free or salt form, e.g.,
as acid addition salts. In this specification unless otherwise indicated,
language such as "Compounds of the Invention" is to be understood as
embracing the compounds in any form, for example free or acid addition
salt form, or where the compounds contain acidic substituents, in base
addition salt form. The Compounds of the Invention are intended for use
as pharmaceuticals, therefore pharmaceutically acceptable salts are
preferred. Salts which are unsuitable for pharmaceutical uses may be
useful, for example, for the isolation or purification of free Compounds
of the Invention or their pharmaceutically acceptable salts, are
therefore also included. In a particular embodiment, the salt of the
compounds of the invention is a formic acid addition salt.

[0465] Compounds of the Invention may in some cases also exist in prodrug
form. A prodrug form is compound which converts in the body to a Compound
of the Invention. For example when the Compounds of the Invention contain
hydroxy or carboxy substituents, these substituents may form
physiologically hydrolysable and acceptable esters. As used herein,
"physiologically hydrolysable and acceptable ester" means esters of
Compounds of the Invention which are hydrolysable under physiological
conditions to yield acids (in the case of Compounds of the Invention
which have hydroxy substituents) or alcohols (in the case of Compounds of
the Invention which have carboxy substituents) which are themselves
physiologically tolerable at doses to be administered. Therefore, wherein
the Compound of the Invention contains a hydroxy group, for example,
Compound-OH, the acyl ester prodrug of such compound, for example,
Compound-O--C(O)--C1-4alkyl, can hydrolyze in the body to form
physiologically hydrolysable alcohol (Compound-OH) on the one hand and
acid on the other (e.g., HOC(O)--C1-4alkyl). Alternatively, wherein
the Compound of the Invention contains a carboxylic acid, for example,
Compound-C(O)OH, the acid ester prodrug of such compound, for example,
Compound-C(O)O--C1-4alkyl can hydrolyze to form Compound-C(O)OH and
HO--C1-4alkyl. As will be appreciated the term thus embraces
conventional pharmaceutical prodrug forms.

[0466] The invention also provides methods of making the Compounds of the
Invention and methods of using the Compounds of the Invention for
treatment of diseases and disorders as set forth below (especially
treatment of diseases characterized by reduced dopamine D1 receptor
signaling activity, such as Parkinson's disease, Tourette's Syndrome,
Autism, fragile X syndrome, ADHD, restless leg syndrome, depression,
cognitive impairment of schizophrenia, narcolepsy and diseases that may
be alleviated by the enhancement of progesterone-signaling such as female
sexual dysfunction), or a disease or disorder such as psychosis or
glaucoma). This list is not intended to be exhaustive and may include
other diseases and disorders as set forth below.

[0467] In another embodiment, the invention further provides a
pharmaceutical composition comprising a Compound of the Invention, in
free or pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

Methods of Making Compounds of the Invention

[0468] The compounds of the Invention and their pharmaceutically
acceptable salts may be made using the methods as described and
exemplified herein and by methods similar thereto and by methods known in
the chemical art. Such methods include, but not limited to, those
described below. If not commercially available, starting materials for
these processes may be made by procedures, which are selected from the
chemical art using techniques which are similar or analogous to the
synthesis of known compounds. Various starting materials and/or Compounds
of the Invention may be prepared using methods described in
PCT/US2009/06438 (WO 2010/065148). All references cited herein are hereby
incorporated by reference in their entirety.

[0469] The Compounds of the Invention include their enantiomers,
diastereoisomers and racemates, as well as their polymorphs, hydrates,
solvates and complexes. Some individual compounds within the scope of
this invention may contain double bonds. Representations of double bonds
in this invention are meant to include both the E and the Z isomer of the
double bond. In addition, some compounds within the scope of this
invention may contain one or more asymmetric centers. This invention
includes the use of any of the optically pure stereoisomers as well as
any combination of stereoisomers.

[0470] As will be appreciated by those skilled in the art, the Compounds
of the Invention may exhibit keto-enol tautomerization. Therefore, the
invention as defined in the present invention is to be understood as
embracing both the structures as setforth herewith and their tautomeric
forms.

[0471] It is also intended that the Compounds of the Invention encompass
their stable and unstable isotopes. Stable isotopes are nonradioactive
isotopes which contain one additional neutron compared to the abundant
nuclides of the same species (i.e., element). It is expected that the
activity of compounds comprising such isotopes would be retained, and
such compound would also have utility for measuring pharmacokinetics of
the non-isotopic analogs. For example, the hydrogen atom at a certain
position on the Compounds of the Invention may be replaced with deuterium
(a stable isotope which is non-radioactive). Examples of known stable
isotopes include, but not limited to, deuterium, 13C, 15N,
18O. Alternatively, unstable isotopes, which are radioactive
isotopes which contain additional neutrons compared to the abundant
nuclides of the same species (i.e., element), e.g., 123I, 131I,
125I, 11C, 18F, may replace the corresponding abundant
species, e.g., I, C and F respectively. Another example of useful isotope
of the compound of the invention is the 11C isotope. These radio
isotopes are useful for radio-imaging and/or pharmacokinetic studies of
the compounds of the invention. Methods of making isotopes of PDE1
inhibitors disclosed in WO 2011/043816, the contents of which are
incorporated by reference in their entirety, may be used for making the
isotopes of the compounds of the current invention

[0472] Melting points are uncorrected and (dec) indicates decomposition.
Temperature are given in degrees Celsius (° C.); unless otherwise
stated, operations are carried out at room or ambient temperature, that
is, at a temperature in the range of 18-25° C. Chromatography
means flash chromatography on silica gel; thin layer chromatography (TLC)
is carried out on silica gel plates. NMR data is in the delta values of
major diagnostic protons, given in parts per million (ppm) relative to
tetramethylsilane (TMS) as an internal standard. Conventional
abbreviations for signal shape are used. Coupling constants (J) are given
in Hz. For mass spectra (MS), the lowest mass major ion is reported for
molecules where isotope splitting results in multiple mass spectral peaks
Solvent mixture compositions are given as volume percentages or volume
ratios. In cases where the NMR spectra are complex, only diagnostic
signals are reported.

[0473] Terms and abbreviations:

[0474] BuLi=n-butyllithium

[0475] ButOH=tert-butyl alcohol,

[0476] CAN=ammonium cerium (IV) nitrate,

[0477] DIPEA=diisopropylethylamine,

[0478] DMF=N,N-dimethylforamide,

[0479] DMSO=dimethyl sulfoxide,

[0480] Et2O=diethyl ether,

[0481] EtOAc=ethyl acetate,

[0482] equiv.=equivalent(s),

[0483] h=hour(s),

[0484] HPLC=high performance liquid chromatography,

[0485] LDA=lithium diisopropylamide

[0486] MeOH=methanol,

[0487] NBS=N-bromosuccinimide

[0488] NCS=N-chlorosuccinimide

[0489] NaHCO3=sodium bicarbonate,

[0490] NH4OH=ammonium hydroxide,

[0491] Pd2(dba)3=tris[dibenzylideneacetone]dipalladium(0)

[0492] PMB=p-methoxybenzyl,

[0493] POCl3=phosphorous oxychloride,

[0494] SOCl2=thionyl
chloride,

[0495] TFA=trifluoroacetic acid,

[0496] THF=tetrahedrofuran.

[0497] The synthetic methods in this invention are illustrated below. The
significances for the R groups are as set forth above for formula II-A or
II-B unless otherwise indicated.

[0498] In an aspect of the invention, Compounds of the invention, e.g., a
Compound of Formulae II-A and II-B or any of the formulae disclosed
herein may be formed by reacting a compound of 1-A and 1-B respectively
with for example a R5--X in a solvent such as DMF and a base such as
K2CO3 at room temperature or with heating:

##STR00016##

wherein all the substituents are as defined previously; L is oxy (--O--);
X is a leaving group such as a halogen, mesylate, or tosylate.

[0499] Alternatively, compounds II-A and II-B may be synthesized by
reacting a compound of 1-C and 1-D respectively with for example a
R6-L-H in a solvent such as dioxane or in neat condition with
heating:

##STR00017##

wherein all the substituents are as defined previously; L is oxy (--O--);
X is a leaving group such as a halogen group.

[0500] Compound 1-C, e.g., wherein Q is C(═O) and X is a chloro group,
may be prepared by, e.g., reacting compound I-E with a chlorinating
reagent such as hexachloroethane in the presence of a strong base or
lithium reagent such as LiHMDS. Compound 1-D, e.g., wherein Q is
C(═O) and X is a chloro group, may be prepared by, e.g., reacting
compound I-F with a chlorinating reagent such NCS in a solvent such as
CCl4. Sometimes, R5 can be a protective group such as a
para-methoxybenzyl (PMB) group. Under this circumstance, compound 1-C or
1-D with the PMB substituent as R5 can be deprotected using a
reagent such as TFA/TFMSA, and then reacts with a different R5X
under basic conditions for rapidly synthesizing 1-C or 1-D analogs.

##STR00018##

[0501] Compounds (I)-E and (I)-F may be formed by reacting a compound of
2-A and 2-B respectively with for example a R5--X in a solvent such
as DMF and a base such as K2CO3 at room temperature or with
heating:

##STR00019##

wherein all the substituents are as defined previously; X is a leaving
group such as a halogen group.

[0502] Intermediate 2, e.g., wherein Q is C(═O) may be prepared by,
e.g., reacting Intermediate 3 with a strong base such as sodium hydride
and a reagent such as TsCHR7NC, e.g., toluenesulfonylmethyl
isocyanide, in a solvent such as THF.

##STR00020##

[0503] Intermediate 3 may be prepared by, e.g., reacting Intermediate 4
with a dehydrating reagent such as diethyl azodicarboxylate in the
presence of phosphine ligand such as triphenylphosphine.

##STR00021##

[0504] Intermediate 4 may be made, e.g., by reacting a compound of 5-A
with an amino alcohol in the presence of a strong base, for example, DBU
(1,8-Diazabicyclo[5.4.0]undec-7-ene),

##STR00022##

wherein all the substituents are as defined previously; X is a leaving
group such as a halogen or methylthio group.

[0505] Alternatively, intermediate 4 may be made, e.g., by reacting a
compound of 5-B with an amino alcohol in the presence of a strong base,
for example, DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) and a coupling
reagent such as BOP at room temperature.

##STR00023##

[0506] The thione Compounds of the Invention, e.g., Compounds of Formula
II-A or II-B wherein Q is C(═S) may then be prepared by reacting the
Compounds of the Invention wherein Q is C(═O) with P4S10 in
a microwave vial in the presence of a base, e.g., pyridine, and heating
the mixture to an elevated temperature, e.g., in a microwave, e.g., to
about 150° C. The imine compounds of the Invention, e.g.,
Compounds of Formula II-A or II-B, wherein Q is C(═N(R20)) may
in turn be converted from the thione derivative (i.e., Compounds of
Formula II-A or II-B, respectively, wherein with Q is C(═S)), by
reacting the thione derivative with NH2(R20) in the presence of
HgCl2, e.g., in a solvent such as THF, and heating the reaction
mixture to an elevated temperature, e.g., in a microwave, e.g., to about
110° C.

[0508] The invention thus provides methods of making Compounds of Formula
II-A or II-B, for example, comprising

[0509] (i) reacting Intermediate
1-A or 1-B, respectively, with a compound of formula R5--X wherein L
is oxy (--O--) and X is a leaving group, e.g., halogen, mesylate, or
tosylate, R5 is as defined above in Formula II-A or II-B, e.g.,
under basic conditions, for example:

##STR00024##

[0510] Alternative methods of making the compounds of the invention,
particularly constructing the bottom (imidazole) ring of compounds of the
compounds of the invention, may be found in U.S. Provisional Applications
61/349,952, which discloses methods of making similar PDE1 inhibitors,
the contents of which provisional application are incorporated by
reference in their entirety.

[0511] Methods of Using Compounds of the Invention

[0512] The Compounds of the Invention, any of the compounds disclosed
herein e.g., any of Compounds of Formula II-A or II-B, e.g., any of
1.1-1.84, or any of III-A, III-B, IV-A, IV-B, V-A, V-B, VI-A, VI-B,
VII-A, VII-B, VIII-A, VIII-B, IX-A, IX-B, X-A, X-B, in free or salt form
are useful in the treatment of diseases characterized by disruption of or
damage to cAMP and cGMP mediated pathways, e.g., as a result of increased
expression of PDE1 or decreased expression of cAMP and cGMP due to
inhibition or reduced levels of inducers of cyclic nucleotide synthesis,
such as dopamine and nitric oxide (NO). By preventing the degradation of
cAMP and cGMP by PDE1B, thereby increasing intracellular levels of cAMP
and cGMP, the Compounds of the Invention potentiate the activity of
cyclic nucleotide synthesis inducers.

[0513] The invention provides methods of treatment of any one or more of
the following conditions:

[0519] (vi) Any disease or condition characterized by
reduced dopamine D1 receptor signaling activity, comprising administering
an effective amount of a Compound of the Invention, e.g., a compound
according to any of Formula II-A or II-B, e.g., any of 1.1-1.84, or any
of III-A, III-B, IV-A, IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B, VIII-A,
VIII-B, IX-A, IX-B, X-A, X-B, XI-A or XI-B, in free or pharmaceutically
acceptable salt form, to a human or animal patient in need thereof.

[0520] In an especially preferred embodiment, the invention provides
methods of treatment or prophylaxis for narcolepsy. In this embodiment,
PDE 1 Inhibitors may be used as a sole therapeutic agent, but may also be
used in combination or for co-administration with other active agents.
Thus, the invention further comprises a method of treating narcolepsy
comprising administering simultaneously, sequentially, or
contemporaneously administering therapeutically effective amounts of

[0521] (i) a PDE 1 Inhibitor, e.g., a compound according to any of
Formula II-A or II-B, e.g., any of 1.1-1.84, or any of III-A, III-B,
IV-A, IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B, VIII-A, VIII-B, IX-A,
IX-B, X-A, X-B, XI-A or XI-B, and

[0523] In another embodiment, the invention further provides methods of
treatment or prophylaxis of a condition which may be alleviated by the
enhancement of the progesterone signaling comprising administering an
effective amount of a Compound of the Invention, in free or
pharmaceutically acceptable salt form, to a human or animal patient in
need thereof. In still another embodiment, the invention further provides
methods of treatment or prophylaxis of a condition which may be
alleviated by the enhancement of the progesterone signaling comprising
administering an effective amount of a Compound of the Invention, in free
or pharmaceutically acceptable salt form, to a human or animal patient in
need thereof. Disease or condition that may be ameliorated by enhancement
of progesterone signaling include, but are not limited to, female sexual
dysfunction, secondary amenorrhea (e.g., exercise amenorrhoea,
anovulation, menopause, menopausal symptoms, hypothyroidism),
pre-menstrual syndrome, premature labor, infertility, for example
infertility due to repeated miscarriage, irregular menstrual cycles,
abnormal uterine bleeding, osteoporosis, autoimmmune disease, multiple
sclerosis, prostate enlargement, prostate cancer, and hypothyroidism. For
example, by enhancing progesterone signaling, the PDE 1 inhibitors may be
used to encourage egg implantation through effects on the lining of
uterus, and to help maintain pregnancy in women who are prone to
miscarriage due to immune response to pregnancy or low progesterone
function. The novel PDE 1 inhibitors, e.g., as described herein, may also
be useful to enhance the effectiveness of hormone replacement therapy,
e.g., administered in combination with estrogen/estradiol/estriol and/or
progesterone/progestins in postmenopausal women, and estrogen-induced
endometrial hyperplasia and carcinoma. The methods of the invention are
also useful for animal breeding, for example to induce sexual receptivity
and/or estrus in a nonhuman female mammal to be bred.

[0524] In this embodiment, PDE 1 Inhibitors may be used in the foregoing
methods of treatment or prophylaxis as a sole therapeutic agent, but may
also be used in combination or for co-administration with other active
agents, for example in conjunction with hormone replacement therapy.
Thus, the invention further comprises a method of treating disorders that
may be ameliorated by enhancement of progesterone signaling comprising
administering simultaneously, sequentially, or contemporaneously
administering therapeutically effective amounts of

[0525] (i) a PDE 1
Inhibitor, e.g., a compound according to any of Formula II-A or II-B,
e.g., any of 1.1-1.84, or any of III-A, III-B, IV-A, IV-B, V-A, V-B,
VI-A, VI-B, VII-A, VII-B, VIII-A, VIII-B, IX-A, IX-B, X-A, X-B, XI-A or
XI-B, and

[0527] The invention also provides a method for enhancing or potentiating
dopamine D1 intracellular signaling activity in a cell or tissue
comprising contacting said cell or tissue with an amount of a Compound of
the Invention, in free or salt form sufficient to inhibit PDE1B activity.

[0528] The invention also provides a method for treating a PDE1-related,
especially PDE1B-related disorder, a dopamine D1 receptor intracellular
signaling pathway disorder, or disorders that may be alleviated by the
enhancement of the progesterone signaling pathway in a patient in need
thereof comprising administering to the patient an effective amount of a
Compound of the Invention, in free or pharmaceutically acceptable salt
form that inhibits PDE1B, wherein PDE1B activity modulates
phosphorylation of DARPP-32 and/or the GluR1 AMPA receptor.

[0529] "The Compound of the Invention" or "a PDE1 Inhibitor of the
Invention" referred to herein includes optionally substituted (1- or
3-oxy)-4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or
4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or (1- or
3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or
4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, or a Compound of
Formula II-A or II-B, e.g., any of 1.1-1.84, or any of III-A, III-B,
IV-A, IV-B, V-A, V-B, VI-A, VI-B, VII-A, VII-B, VIII-A, VIII-B, IX-A,
IX-B, X-A, X-B, XI-A or XI-B, in free or (pharmaceutically) acceptable
salt form.

[0530] In another aspect, the invention also provides a method for the
treatment for glaucoma or elevated intraocular pressure comprising
topical administration of a therapeutically effective amount of a
phosphodiesterase type I (PDE1) Inhibitor of the Invention, in free or
pharmaceutically acceptable salt form, in an ophthalmically compatible
carrier to the eye of a patient in need thereof. However, treatment may
alternatively include a systemic therapy. Systemic therapy includes
treatment that can directly reach the bloodstream, or oral methods of
administration, for example.

[0531] The invention further provides a pharmaceutical composition for
topical ophthalmic use comprising a PDE1 inhibitor; for example an
ophthalmic solution, suspension, cream or ointment comprising a PDE1
Inhibitor of the Invention, in free or ophthalmologically acceptable salt
form, in combination or association with an ophthalmologically acceptable
diluent or carrier.

[0532] Optionally, the PDE1 Inhibitor of the Invention may be administered
sequentially or simultaneously with a second drug useful for treatment of
glaucoma or elevated intraocular pressure. Where two active agents are
administered, the therapeutically effective amount of each agent may be
below the amount needed for activity as monotherapy. Accordingly, a
subthreshold amount (i.e., an amount below the level necessary for
efficacy as monotherapy) may be considered therapeutically effective and
also may also be referred alternatively as an effective amount. Indeed,
an advantage of administering different agents with different mechanisms
of action and different side effect profiles may be to reduce the dosage
and side effects of either or both agents, as well as to enhance or
potentiate their activity as monotherapy.

[0533] The invention thus provides the method of treatment of a condition
selected from glaucoma and elevated intraocular pressure comprising
administering to a patient in need thereof an effective amount, e.g., a
subthreshold amount, of an agent known to lower intraocular pressure
concomitantly, simultaneously or sequentially with an effective amount,
e.g., a subthreshold amount, of a PDE1 Inhibitor of the Invention, in
free or pharmaceutically acceptable salt form, such that amount of the
agent known to lower intraocular pressure and the amount of the PDE1
inhibitor in combination are effective to treat the condition.

[0534] In one embodiment, one or both of the agents are administered
topically to the eye. Thus the invention provides a method of reducing
the side effects of treatment of glaucoma or elevated intraocular
pressure by administering a reduced dose of an agent known to lower
intraocular pressure concomitantly, simultaneously or sequentially with
an effective amount of a PDE1 inhibitor. However, methods other than
topical administration, such as systemic therapeutic administration, may
also be utilized.

[0535] The optional additional agent or agents for use in combination with
a PDE1 Inhibitor of the Invention may, for example, be selected from the
existing drugs comprise typically of instillation of a prostaglandin,
pilocarpine, epinephrine, or topical beta-blocker treatment, e.g. with
timolol, as well as systemically administered inhibitors of carbonic
anhydrase, e.g. acetazolamide. Cholinesterase inhibitors such as
physostigmine and echothiopate may also be employed and have an effect
similar to that of pilocarpine. Drugs currently used to treat glaucoma
thus include, e.g.,

[0542] 7. Physostigmine is also used to treat glaucoma and
delayed gastric emptying.

[0543] For example, the invention provides pharmaceutical compositions
comprising a PDE1 Inhibitor of the Invention and an agent selected from
(i) the prostanoids, unoprostone, latanoprost, travoprost, or
bimatoprost; (ii) an alpha adrenergic agonist such as brimonidine,
apraclonidine, or dipivefrin and (iii) a muscarinic agonist, such as
pilocarpine. For example, the invention provides ophthalmic formulations
comprising a PDE-1 Inhibitor of the Invention together with bimatoprost,
abrimonidine, brimonidine, timolol, or combinations thereof, in free or
ophthamalogically acceptable salt form, in combination or association
with an ophthamologically acceptable diluent or carrier. In addition to
selecting a combination, however, a person of ordinary skill in the art
can select an appropriate selective receptor subtype agonist or
antagonist. For example, for alpha adrenergic agonist, one can select an
agonist selective for an alpha 1 adrenergic receptor, or an agonist
selective for an alpha2 adrenergic receptor such as brimonidine, for
example. For a beta-adrenergic receptor antagonist, one can select an
antagonist selective for either β1, or β2, or
β3, depending on the appropriate therapeutic application. One
can also select a muscarinic agonist selective for a particular receptor
subtype such as M1-M5.

[0544] The PDE 1 Inhibitor of the Invention may be administered in the
form of an ophthalmic composition, which includes an ophthalmic solution,
cream or ointment. The ophthalmic composition may additionally include an
intraocular-pressure lowering agent.

[0545] In yet another example, the PDE-1 Inhibitors of the Invention
disclosed may be combined with a subthreshold amount of an intraocular
pressure-lowering agent which may be a bimatoprost ophthalmic solution, a
brimonidine tartrate ophthalmic solution, or brimonidine tartrate/timolol
maleate ophthalmic solution.

[0546] In addition to the above-mentioned methods, it has also been
surprisingly discovered that PDE1 Inhibitors of the Invention are useful
to treat psychosis, for example, any conditions characterized by
psychotic symptoms such as hallucinations, paranoid or bizarre delusions,
or disorganized speech and thinking, e.g., schizophrenia, schizoaffective
disorder, schizophreniform disorder, psychotic disorder, delusional
disorder, and mania, such as in acute manic episodes and bipolar
disorder. Without intending to be bound by any theory, it is believed
that typical and atypical antipsychotic drugs such as clozapine primarily
have their antagonistic activity at the dopamine D2 receptor. PDE1
inhibitors, however, primarily act to enhance signaling at the dopamine
D1 receptor. By enhancing D1 receptor signaling, PDE1 inhibitors can
increase NMDA receptor function in various brain regions, for example in
nucleus accumbens neurons and in the prefrontal cortex. This enhancement
of function may be seen for example in NMDA receptors containing the NR2B
subunit, and may occur e.g., via activation of the Src and protein kinase
A family of kinases.

[0547] Therefore, the invention provides a new method for the treatment of
psychosis, e.g., schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder, and
mania, such as in acute manic episodes and bipolar disorder, comprising
administering a therapeutically effective amount of a phosphodiesterase-1
(PDE1) Inhibitor of the Invention, in free or pharmaceutically acceptable
salt form, to a patient in need thereof.

[0548] PDE 1 Inhibitors of the Invention may be used in the foregoing
methods of treatment prophylaxis as a sole therapeutic agent, but may
also be used in combination or for co-administration with other active
agents. Thus, the invention further comprises a method of treating
psychosis, e.g., schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder, or
mania, comprising administering simultaneously, sequentially, or
contemporaneously administering therapeutically effective amounts of:

[0549] (i) a PDE 1 Inhibitor of the Invention, in free or
pharmaceutically acceptable salt form; and

[0557] in free or
pharmaceutically acceptable salt form, to a patient in need thereof.

[0558] In a particular embodiment, the Compounds of the Invention are
particularly useful for the treatment or prophylaxis of schizophrenia.

[0559] Compounds of the Invention, in free or pharmaceutically acceptable
salt form, are particularly useful for the treatment of Parkinson's
disease, schizophrenia, narcolepsy, glaucoma and female sexual
dysfunction.

[0560] In still another aspect, the invention provides a method of
lengthening or enhancing growth of the eyelashes by administering an
effective amount of a prostaglandin analogue, e.g., bimatoprost,
concomitantly, simultaneously or sequentially with an effective amount of
a PDE1 Inhibitor of the Invention, in free or pharmaceutically acceptable
salt form, to the eye of a patient in need thereof.

[0561] In yet another aspect, the invention provides a method for the
treatment or prophylaxis of traumatic brain injury comprising
administering a therapeutically effective amount of a Compound of the
Invention, in free or pharmaceutically acceptable salt form, to a patient
in need thereof. Traumatic brain injury (TBI) encompasses primary injury
as well as secondary injury, including both focal and diffuse brain
injuries. Secondary injuries are multiple, parallel, interacting and
interdependent cascades of biological reactions arising from discrete
subcellular processes (e.g., toxicity due to reactive oxygen species,
overstimulation of glutamate receptors, excessive influx of calcium and
inflammatory upregulation) which are caused or exacerbated by the
inflammatory response and progress after the initial (primary) injury.
Abnormal calcium homeostasis is believed to be a critical component of
the progression of secondary injury in both grey and white matter. For a
review of TBI, see Park et al., CMAJ (2008) 178(9):1163-1170, the
contents of which are incorporated herein in their entirety. Studies have
shown that the cAMP-PKA signaling cascade is downregulated after TBI and
treatment of PDE IV inhibitors such as rolipram to raise or restore cAMP
level improves histopathological outcome and decreases inflammation after
TBI. As Compounds of the present invention is a PDE1 inhibitor, it is
believed that these compounds are also useful for the treatment of TBI,
e.g., by restoring cAMP level and/or calcium homeostasis after traumatic
brain injury.

[0562] The present invention also provides

[0563] (i) a Compound of the
Invention, in free or pharmaceutically acceptable salt form, for use as a
pharmaceutical, for example for use in any method or in the treatment of
any disease or condition as hereinbefore set forth,

[0564] (ii) the use
of a Compound of the Invention, in free or pharmaceutically acceptable
salt form, in the manufacture of a medicament for treating any disease or
condition as hereinbefore set forth,

[0565] (iii) a pharmaceutical
composition comprising a Compound of the Invention, in free or
pharmaceutically acceptable salt form, in combination or association with
a pharmaceutically acceptable diluent or carrier, and

[0566] (iv) a
pharmaceutical composition comprising a Compound of the Invention, in
free or pharmaceutically acceptable salt form, in combination or
association with a pharmaceutically acceptable diluent or carrier for use
in the treatment of any disease or condition as hereinbefore set forth.

[0568] The invention also provides use of a Compound of the Invention, in
free or pharmaceutically acceptable salt form, (for the manufacture of a
medicament) for the treatment or prophylactic treatment of:

[0572] The words "treatment" and "treating" are to be understood
accordingly as embracing prophylaxis and treatment or amelioration of
symptoms of disease as well as treatment of the cause of the disease.

[0573] For methods of treatment, the word "effective amount" is intended
to encompass a therapeutically effective amount to treat a specific
disease or disorder.

[0574] The term "pulmonary hypertension" is intended to encompass
pulmonary arterial hypertension.

[0575] The term "patient" include human or non-human (i.e., animal)
patient. In particular embodiment, the invention encompasses both human
and nonhuman. In another embodiment, the invention encompasses nonhuman.
In other embodiment, the term encompasses human.

[0576] The term "comprising" as used in this disclosure is intended to be
open-ended and does not exclude additional, unrecited elements or method
steps.

[0577] Compounds of the Invention are in particular useful for the
treatment of Parkinson's disease, narcolepsy and female sexual
dysfunction.

[0578] Compounds of the Invention, in free or pharmaceutically acceptable
salt form may be used as a sole therapeutic agent, but may also be used
in combination or for co-administration with other active agents. For
example, as Compounds of the Invention potentiate the activity of D1
agonists, such as dopamine, they may be simultaneously, sequentially, or
contemporaneously administered with conventional dopaminergic
medications, such as levodopa and levodopa adjuncts (carbidopa, COMT
inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics,
e.g., in the treatment of a patient having Parkinson's disease. In
addition, the novel PDE 1 inhibitors, e.g., as described herein, may also
be administered in combination with estrogen/estradiol/estriol and/or
progesterone/progestins to enhance the effectiveness of hormone
replacement therapy or treatment of estrogen-induced endometrial
hyperplasia or carcinoma.

[0579] Dosages employed in practicing the present invention will of course
vary depending, e.g. on the particular disease or condition to be
treated, the particular Compound of the Invention used, the mode of
administration, and the therapy desired. Compounds of the Invention may
be administered by any suitable route, including orally, parenterally,
transdermally, or by inhalation, but are preferably administered orally.
In general, satisfactory results, e.g. for the treatment of diseases as
hereinbefore set forth are indicated to be obtained on oral
administration at dosages of the order from about 0.01 to 2.0 mg/kg. In
larger mammals, for example humans, an indicated daily dosage for oral
administration will accordingly be in the range of from about 0.75 to 150
mg, conveniently administered once, or in divided doses 2 to 4 times,
daily or in sustained release form. Unit dosage forms for oral
administration thus for example may comprise from about 0.2 to 75 or 150
mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of the
Invention, together with a pharmaceutically acceptable diluent or carrier
therefor.

[0580] Pharmaceutical compositions comprising Compounds of the Invention
may be prepared using conventional diluents or excipients and techniques
known in the galenic art. Thus oral dosage forms may include tablets,
capsules, solutions, suspensions and the like.

EXAMPLES

[0581] The synthetic methods for various Compounds of the Present
Invention are illustrated below. Other compounds of the Invention and
their salts may be made using the methods as similarly described below
and/or by methods similar to those generally described in the detailed
description and by methods known in the chemical art.

[0584] To a solution of
2-((1R,2R)-2-hydroxycyclopentylamino)-3-methylpyrimidin-4(3H)-one (130
mg, 0.62 mmol) in anhydrous THF (2 mL) is added triphenylphosphine (163
mg, 0.62 mmol). After five minutes, diethyl azodicarboxylate (DEAD, 0.45
mL, 0.93 mmol) in toluene is added dropwise. The mixture is stirred at
room temperature for 2 hours. After solvent is removed under reduced
pressure, the residue is treated with 0.02 N HCl (40 mL). The precipitate
is filtered off, and the filtrate is washed with CH2Cl2. The
aqueous phase is evaporated to dryness under high vacuum to give product
as solids (108 mg, yield 92%), which is used in the next step without
further purification. MS (ESI) m/z 192.1 [M+H].sup.+.

[0585] Sodium hydride (95%, 112 mg, 4.44 mmol) is suspended in 3 mL of
anhydrous THF, and then a mixture of
(3aS,8aR)-7-Methyl-1,2,3,3a,7,8a-hexahydro-3b,7,8-triaza-cyclopenta[a]ind-
en-6-one (283 mg, 1.48 mmol) and p-toluenesulfonylmethyl isocyanide (97%,
347 mg, 1.77 mmol) in 5 mL of anhydrous THF is added dropwise. The
mixture is stirred at room temperature for an hour, and then quenched
with water. The mixture is extracted with CH2Cl2 five times
(5×10 mL). The combined organic phase is washed with brine, and
then dried with anhydrous Na2SO4. After filtration, the
filtrate is evaporated to dryness under reduced pressure to give crude
product (320 mg, yield 94%) as brown solids, which is used in the next
step without further purification. MS (ESI) m/z 231.1 [M+H].sup.+.

[0586] A suspension of
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-cyclopent[4,5]imidazo[1,2-a]py-
rrolo[4,3-e]pyrimidin-4(2H)-one (500 mg, 2.2 mmol),
1-(chloromethyl)-4-methoxybenzene (0.38 mL, 2.8 mmol) and cesium
carbonate (1.3 mg, 1.8 mmol) in anhydrous DMF is stirred at room
temperature for 3 h. The mixture is diluted with saturated NaHCO3
aqueous solution, and then extracted with CH2Cl2/MeOH (10:1)
three times. The combined organic phase is dried over anhydrous sodium
sulfate, and then filtered through a layer of celite. The filtrate is
concentrated, and then purified by silica-gel column chromatography to
give product as beige solids. MS (ESI) m/z 351.2 [M+11].sup.+.

[0589] Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin dependent
phosphodiesterase enzyme that converts cyclic guanosine monophosphate
(cGMP) to 5'-guanosine monophosphate (5'-GMP). PDE1B can also convert a
modified cGMP substrate, such as the fluorescent molecule
cGMP-fluorescein, to the corresponding GMP-fluorescein. The generation of
GMP-fluorescein from cGMP-fluorescein can be quantitated, using, for
example, the IMAP (Molecular Devices, Sunnyvale, Calif.)
immobilized-metal affinity particle reagent.

[0590] Briefly, the IMAP reagent binds with high affinity to the free
5'-phosphate that is found in GMP-fluorescein and not in
cGMP-fluorescein. The resulting GMP-fluorescein--IMAP complex is large
relative to cGMP-fluorescein. Small fluorophores that are bound up in a
large, slowly tumbling, complex can be distinguished from unbound
fluorophores, because the photons emitted as they fluoresce retain the
same polarity as the photons used to excite the fluorescence.

[0591] In the phosphodiesterase assay, cGMP-fluorescein, which cannot be
bound to IMAP, and therefore retains little fluorescence polarization, is
converted to GMP-fluorescein, which, when bound to IMAP, yields a large
increase in fluorescence polarization (Δmp) Inhibition of
phosphodiesterase, therefore, is detected as a decrease in Δmp.

[0592] Enzyme Assay

Materials: All chemicals are available from Sigma-Aldrich (St. Louis,
Mo.) except for IMAP reagents (reaction buffer, binding buffer, FL-GMP
and IMAP beads), which are available from Molecular Devices (Sunnyvale,
Calif.). Assay: 3',5'-cyclic-nucleotide-specific bovine brain
phosphodiesterase (Sigma, St. Louis, Mo.) is reconstituted with 50%
glycerol to 2.5 U/ml. One unit of enzyme will hydrolyze 1.0 μmole of
3',5'-cAMP to 5'-AMP per min at pH 7.5 at 30° C. One part enzyme
is added to 1999 parts reaction buffer (30 μM CaCl2, 10 U/ml of
calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM MgCl2, 0.1%
BSA, 0.05% NaN3) to yield a final concentration of 1.25 mU/ml. 99
μl of diluted enzyme solution is added into each well in a flat bottom
96-well polystyrene plate to which 1 μl of test compound dissolved in
100% DMSO is added. The compounds are mixed and pre-incubated with the
enzyme for 10 min at room temperature.

[0593] The FL-GMP conversion reaction is initiated by combining 4 parts
enzyme and inhibitor mix with 1 part substrate solution (0.225 μM) in
a 384-well microtiter plate. The reaction is incubated in dark at room
temperature for 15 min. The reaction is halted by addition of 60 μl of
binding reagent (1:400 dilution of IMAP beads in binding buffer
supplemented with 1:1800 dilution of antifoam) to each well of the
384-well plate. The plate is incubated at room temperature for 1 hour to
allow IMAP binding to proceed to completion, and then placed in an
Envision multimode microplate reader (PerkinElmer, Shelton, Conn.) to
measure the fluorescence polarization (Δmp).

[0594] A decrease in GMP concentration, measured as decreased Δmp,
is indicative of inhibition of PDE activity. IC50 values are
determined by measuring enzyme activity in the presence of 8 to 16
concentrations of compound ranging from 0.0037 nM to 80,000 nM and then
plotting drug concentration versus ΔmP, which allows IC50
values to be estimated using nonlinear regression software (XLFit; IDBS,
Cambridge, Mass.). The exemplified compound of the invention has an
IC50 value of 15 nM, against PDE1A.

Example 3

PDE1 Inhibitor Effect on Sexual Response in Female Rats

[0595] The effect of PDE1 inhibitors on Lordosis Response in female rats
may be measured as described in Mani, et al., Science (2000) 287: 1053.
Ovariectomized and cannulated wild-type rats are primed with 2 μg
estrogen followed 24 hours later by intracerebroventricular (icv)
injection of progesterone (2 μg), PDE1 inhibitors of the present
invention (0.1 mg, 1.0 mg or 2.5 mg) or sesame oil vehicle (control). The
rats may be tested for lordosis response in the presence of male rats.
Lordosis response is quantified by the lordosis quotient (LQ=number of
lordosis/10 mounts×100).

Patent applications by Jun Zhao, New York, NY US

Patent applications by Peng Li, New York, NY US

Patent applications by Intra-Cellular Therapies, Inc.

Patent applications in class With additional active ingredient

Patent applications in all subclasses With additional active ingredient